The candidate, Dr. John B. Sunwoo, is a junior faculty member in the Department of Otolaryngology - Head and Neck Surgery at Washington University. His long-term goal is to understand the critical mechanisms underlying the ability of head and neck cancer to evade the immune system. Previous work by his mentor, Dr. Wayne Yokoyama and by others has indicated that the capacity of NK cells to kill target cells is triggered or co-stimulated by an integral transmembrane protein/receptor on NK cells, called NKG2D. Recent work by two collaborators, Dr. Veronika Groh and Dr. Thomas Spies, has shown that epithelial-type tumors shed a cell surface ligand for NKG2D, called MICA. This solubilized form of MICA (sMICA) can be found in the serum of these patients where it can down-modulate NKG2D and thus, facilitate the evasion of cell-mediated killing. Preliminary work by the applicant has demonstrated that head and neck squamous cell carcinoma (HNSCC) cells express MICA and that incubation of NK cells in the serum of these patients leads to the down-modulation of NKG2D. Thus, it is the hypothesis of the applicant that these tumors shed MICA into the circulation and that this is a critical mechanism used by these tumor to evade the immune system. The overall objectives of this proposal are to examine the role of sMICA in the pathogenesis of head and neck cancer, focusing on oral squamous cell carcinoma. Specific Aim 1 will assess the production of sMICA in patients with this malignancy, its effects on NKG2D and NK cell function, and its effects on clinical course. Specific Aim 2 will establish a murine model of tumor development in the setting of solubilized NKG2D ligand. This aim will not only examine the role of this molecule in actual tumorigenesis, but will also provide a system that can be manipulated in future studies. Specific Aim 3 will examine the highly polymorphic nature of MICA and assess for associations with sMICA production, affinity for NKG2D, NK cell dysfunction, and clinical features of oral squamous cell carcinoma.